The present invention relates generally to the field of cell signaling pathways involved in cancer, and more specifically to identifying ligands involved in the regulation of Wnt/β-catenin signaling, and to detecting the ability of a compound to modulate the activity of a receptor in a cell.
The Wnt/β-catenin signaling pathway is essential for development and stem cell survival and is aberrantly activated in cancer. The Wnt/β-catenin signaling pathway, also called the canonical pathway of Wnt signaling, is one of the most fundamental mechanisms that control cell proliferation and cell fate determination during embryonic development and tissue generation. Signaling of this pathway is initiated by the binding of a Wnt ligand to its co-receptors, Frizzled and LRP5/6, to form a complex that recruits Dishevelled (Dsh), Axin and GSK3, and then internalizes into large multivesicular bodies. The process leads to inhibition of GSK3 activity and thus accumulation of unphosphorylated β-catenin which enters the nucleus. Nuclear β-catenin interacts with transcription factors, such as LEF/TCF, to activate or repress the transcription of Wnt target genes, which then affect cell proliferation and differentiation and provide feedback control during Wnt signaling.
As normal embryogenesis and development are completed, the Wnt/β-catenin signaling pathway becomes essential for the self-renewal and maintenance of adult stem cells. These stem cells are capable of regenerating all cell types of the tissue in which they reside, and are therefore critical to the repair of injured tissues and to the maintenance of tissues with high turnover such as the skin and intestine. Furthermore, adult stem cells are also believed to be the cells-of-origin for many types of cancer since they are already programmed to divide indefinitely. In analogy to normal tissues, many types of cancer are shown to have a hierarchical structure with only a portion of the cells in a tumor mass, the so-called tumor initiating cells or cancer stem cells (CSCs) that can self-renew and are responsible to generate the heterogeneity of the tumor. Therapeutic approaches that can disrupt the homeostasis of CSCs and eradicate them offer the potential of curing the cancer. The Wnt/β-catenin signaling is frequently over-activated in many types of cancer, and is critical to the survival of cancer stem cells. Therefore, targeting this pathway has long been sought for the development of ant-cancer drugs. However, the approach has been challenging due to the complexity and redundancy of the Wnt-FZD-LRP5/6 ligand-receptor system as well as the lack of specific targets in CSCs.